Variations of calorie restriction for the prevention of pancreatic cancer

预防胰腺癌的热量限制的变化

• 批准号: 7769890
• 负责人: Susan Patricia Lanza-Jacoby
• 金额: $ 17万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769890
• 关键词: Address; Advanced Development; Age; Animal Model; Animals; Apoptosis; Atherosclerosis; Binding Proteins; Biological Markers; Body Weight; Body mass index; Breast; Caloric Restriction; Calories; Carcinoma in Situ; Cell Proliferation; Cells; Chronic; Chronic Disease; Colon; Colon Carcinoma; Computer software; Data; Development; Diagnosis; Dietary Factors; Disease; Ductal Epithelial Cell; EGFR Protein Overexpression; Early Diagnosis; Eating; Energy Intake; Epidermal Growth Factor Receptor; Evaluation; Exhibits; Female; Goals; Growth; Growth Factor; Human; Incidence; Individual; Insulin; Insulin-Like Growth Factor Binding Protein 3; Intake; Intervention; K-ras Oncogene; Laboratory Animals; Lead; Lesion; Life; Life Expectancy; Life Style; Liver; Longevity; Lung Neoplasms; Lymphoma; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammary Neoplasms; Measures; Modeling; Molecular; Mononuclear; Mus; Mutation; NIH Program Announcements; Nimesulide; Nutritional Requirements; Oxidative Stress; PTGS2 gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Pilot Projects; Positron-Emission Tomography; Postmenopause; Premalignant; Prevention; Prevention strategy; Prostatic Neoplasms; Proteins; Rattus; Relative (related person); Reporting; Research; Risk; Risk Factors; Rodent; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Skin; Staging; Stomach; Subgroup; Survival Rate; Tissue Microarray; Transgenic Mice; Transgenic Organisms; Variant; Weight Gain; Work; base; cancer type; feeding; high risk; human FRAP1 protein; improved; inhibitor/antagonist; insulin sensitivity; leukemia; mTOR protein; malignant breast neoplasm; mouse model; neoplastic; outcome forecast; pre-clinical; prevent; protective effect; protein expression; public health relevance; pulmonary function; response; success; tumor; Address; Advanced Development; Age; Animal Model; Animals; Apoptosis; Atherosclerosis; Binding Proteins; Biological Markers; Body Weight; Body mass index; Breast; Caloric Restriction; Calories; Carcinoma in Situ; Cell Proliferation; Cells; Chronic; Chronic Disease; Colon; Colon Carcinoma; Computer software; Data; Development; Diagnosis; Dietary Factors; Disease; Ductal Epithelial Cell; EGFR Protein Overexpression; Early Diagnosis; Eating; Energy Intake; Epidermal Growth Factor Receptor; Evaluation; Exhibits; Female; Goals; Growth; Growth Factor; Human; Incidence; Individual; Insulin; Insulin-Like Growth Factor Binding Protein 3; Intake; Intervention; K-ras Oncogene; Laboratory Animals; Lead; Lesion; Life; Life Expectancy; Life Style; Liver; Longevity; Lung Neoplasms; Lymphoma; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammary Neoplasms; Measures; Modeling; Molecular; Mononuclear; Mus; Mutation; NIH Program Announcements; Nimesulide; Nutritional Requirements; Oxidative Stress; PTGS2 gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Pilot Projects; Positron-Emission Tomography; Postmenopause; Premalignant; Prevention; Prevention strategy; Prostatic Neoplasms; Proteins; Rattus; Relative (related person); Reporting; Research; Risk; Risk Factors; Rodent; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Skin; Staging; Stomach; Subgroup; Survival Rate; Tissue Microarray; Transgenic Mice; Transgenic Organisms; Variant; Weight Gain; Work; base; cancer type; feeding; high risk; human FRAP1 protein; improved; inhibitor/antagonist; insulin sensitivity; leukemia; mTOR protein; malignant breast neoplasm; mouse model; neoplastic; outcome forecast; pre-clinical; prevent; protective effect; protein expression; public health relevance; pulmonary function; response; success; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer progresses over many years, which offers the opportunity for early detection and prevention. Studies have identified elevated body mass index (BMI) as a risk factor for pancreatic cancer. Lower body weights resulting from calorie restriction have long been associated with extended life expectancy and reduced tumor incidence in laboratory animals. Chronic and intermittent calorie restriction have a powerful protective effect against tumor development. This proposal addresses the hypothesis that intermittent calorie restriction will prevent the development and delay progression of preneoplastic to neoplastic lesions by altering select biomarkers. The Kras; Pdx-1Cre mouse model provides an opportunity to study the efficacy of prevention strategies during the preinvasive state. The specific aims are: 1. To determine the effects of intermittent caloric restriction/refeeding and chronic restriction on the developmental progression of preneoplastic to neoplastic lesions in the K-ras; Pdx-1Cre transgenic mice relative to ad libitum fed mice. 2. Determine biomarker levels during each stage of PanIn progression to advanced lesions and whether chronic and intermittent calorie restriction modifies these biomarkers by measuring: a) serum concentrations of IGF-1 and IGFBP-3, b) the extent of proliferation and apoptosis in the pancreases from K-ras; Pdx-1Cre transgenic mice, c) IGF-1 and IGFBP-3 protein levels in pancreatic ductal cells, and d) activation of EGFR, Ras/MAPK, and PI3K/Akt signaling in pancreatic ductal cells using the cutting edge matrix assembly tissue array with AQUA software. Starting at 6-weeks mice will be assigned to: Group 1: ad libitum fed mice, Group 2: intermittent calorie restricted/refed mice fed in 2-week intervals at 50% of the ad libitum caloric intake followed by 2 weeks of ad libitum feeding; and Group 3: Chronic calorie restricted pair fed the average daily food intake that corresponds to the 4-wk restriction/refeeding interval of the intermittent calorie restricted mice. At 52 and 64 weeks of age, we will screen all the mice for the presence of a tumor by PET imaging. At 64 weeks mice in aim 1 will be sacrificed for evaluation of PanIn lesions and biomarkers. For aim 2 subgroups of mice will be sacrificed at 16 and 28 weeks of age to determine progressive changes in activation of EGFR, Ras/MAPK, PI3K/Akt, and mTOR and protein expression of IGF-1 and IGFBP-3 in pancreas by tissue array, proliferation, and serum concentrations of IGF-1 and IGFBP-3. Data obtained from this study will provide the first available information on whether calorie restriction will be of benefit for preventing pancreatic cancer and identification of biomarkers altered by this intervention. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a deadly disease with only 5% of the patients living longer than 5 years. It is a disease with no known cure or strategy to prevent its occurrence. Thus, it is urgent to find ways to prevent this disease. Based upon the success of calorie restriction in preventing many types of cancer, this study will evaluate whether chronic and intermittent calorie restriction will prevent pancreatic cancer by targeting precancerous lesions in a relevant mouse model. Additionally, this study will identify early signaling biomarkers associated with precancerous lesion development and determine whether chronic and intermittent calorie restriction decreased the activation of Ras/MAPK/PI3K, proliferation, apoptosis in the pancreas, and circulating IGF-1.

描述（由申请人提供）：胰腺癌多年来进展，这为早期发现和预防提供了机会。研究已经确定升高的体重指数（BMI）是胰腺癌的危险因素。卡路里限制导致的较低体重长期以来一直与预期寿命延长和实验动物的肿瘤发生率降低有关。慢性和间歇性卡路里限制具有针对肿瘤发育的强大保护作用。该提议解决了以下假设：间歇性卡路里限制将通过改变精选的生物标志物来防止肿瘤肿瘤变性到肿瘤病变的发展和延迟。克拉斯； PDX-1CRE小鼠模型提供了一个机会，可以在侵入性状态下研究预防策略的功效。具体目的是：1。确定间歇性热量限制/重新促进和慢性限制对K-RAS中肿瘤性病变发展的发育进展的影响； PDX-1CRE转基因小鼠相对于自由喂养小鼠。 2.在Panin向晚期病变的每个阶段确定生物标志物水平，以及慢性和间歇性卡路里限制是否通过测量来修饰这些生物标志物：a）IGF-1和IGFBP-3的血清浓度的浓度PDX-1CRE转基因小鼠，c）胰腺导管细胞中的IGF-1和IGFBP-3蛋白水平，d）使用尖端矩阵组装组织组合组织阵列aqua and aqua and aqua阵列中胰腺导管细胞中EGFR，RAS/MAPK和PI3K/MAPK和PI3K/AKT信号传导。从6周开始将小鼠分配给：第1组：双重喂养小鼠，第2组：间歇性卡路里限制/ref的小鼠以2周的间隔为50％的额外热量摄入量的50％，然后进行2周的额外喂养；和第3组：慢性卡路里限制对喂养的平均每日食物摄入量对应于间歇性卡路里受限小鼠的4周限制/重肌间隔。在52周和64周龄时，我们将通过PET成像筛选所有小鼠以在肿瘤中存在。在64周时，AIM 1的小鼠将被牺牲，以评估Panin病变和生物标志物。对于目标，将在16和28周龄上处死2个小鼠的亚组，以确定EGFR，RAS/MAPK，PI3K/AKT的激活逐渐变化，以及IGF-1和IGFBP-3的MTOR和MTOR和蛋白质表达在pancreas中通过组织阵列，增殖，血清和血清浓度IGF-1和IGB-1和IGBP-3在胰腺中的胰腺逐渐变化。从这项研究中获得的数据将提供第一个可用的信息，涉及卡路里限制是否有益于预防胰腺癌和通过这种干预改变的生物标志物的鉴定。公共卫生相关性：胰腺癌是一种致命疾病，只有5％的患者超过5年。它是一种没有已知的治愈或策略来防止其发生的疾病。因此，迫切需要找到预防这种疾病的方法。基于卡路里限制在预防多种类型癌症方面的成功，本研究将评估慢性和间歇性卡路里限制是否会通过靶向相关小鼠模型中的癌性病变来预防胰腺癌。此外，这项研究将确定与癌前病变发育相关的早期信号生物标志物，并确定慢性和间歇性卡路里限制是否会降低RAS/MAPK/PI3K的激活，胰腺中的增殖，凋亡以及循环IGF-1的激活。